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Posts Tagged ‘b-cell’

Greg and I moved back to our home in Vermont today. Now, instead of weekly visits to the hospital in Boston, we’ll only have monthly visits. This would’ve come much earlier had it not been for the (likely) false diagnosis of CMV and the myelosuppressive therapy that ensued, which may well have been key to my contracting the C. difficile that knocked me down so far. But despite all of this, I’m now doing quite well and feeling very strong.

Last Tuesday during my last weekly visit, I was in the room where nurses take vital signs, and a woman was sitting next to me. She was wearing a mask and gloves, and when this sort of thing happens—when two transplant patients are sitting next to each other—there’s this strange E.T.-and-Elliot thing that goes on; we just want to talk to each other. Or in my case: I can tell they’d like to connect with me, and I usually resist this, being a curmudgeon and all. But on Tuesday, the woman sitting next to me just jumped right in. She started asking me questions about my progress since transplant. I was in a pretty good mood that day, but had this happened on practically any other day, I’d probably have perceived this as rude prying. On this day, I saw it as tolerable prying, so we had a chat. During our discussion, she asked me how far along I was since transplant. I told her just over two months; she was quite surprised. She went on to say that she was six months out, and that I looked so good she thought I might be nine or more months since transplant, but certainly ahead of her.

I was pretty surprised by this reaction, and it made me realize that I just didn’t have any frame of reference for how well I’m recovering relative to the average patient. I’ve always thought that I’ve been doing pretty well, but I’ve never really known. So I asked my physician what he thought. He said emphatically that I was doing much, much better than most in terms of recovery, energy level, activity level, and such. In fact, except for the uncontrollable neuropathy and my problems with the treatment for that (more on that later), I don’t have many complaints. I’m more energetic now than I’ve been in ten years, and my red blood cell count is still rather low, but rising steadily, so more energy is yet to come.

So, despite my setbacks—the main one being the serious blow I took from the C. difficile—I seem to have rebounded and my health status has more than “caught up.” My blood cell counts look great for my stage, and my physician has actually started tapering my immunosuppressives, a month or two early. That means my lymphocytes will come on board earlier (but still many months away), which means protection from viruses. But this could also mean that Graft Versus Host Disease (GVHD) is going to hit soon. But GVHD also means Graft Versus Lymphoma effect: All my cells are me, including any remaining cancer cells that are almost certainly floating around. If—or rather, when my new immune system recognizes that it’s in a body of foreign cells and initiates an attack on my whole body, that attack will be on any remaining cancer cells too. In fact, because this attack is mediated by T-lymphocytes—and those cells normally communicate with B-cells when they initiate an immune response—this means that when GVHD does hit, those T-cells will preferentially seek out B-cells during their attack on my body. As I have B-cell lymphoma, those lingering cancerous B-cells will very likely come into contact with those T-cells that are seeking to fight off my cells. When this happens, the T-cells will recognize that my B-cells are foreign too, and some of those T-cells can kill my cancer cells on the spot (so-called, Cytotoxic T-cells).

So, GVHD is kind of a mixed bag. But one thing is certain from the empirical literature: Long-term survivors of stem cell transplants have mild-to-chronic GVHD. These people are far less likely to relapse, and people who have no GVHD are far more likely to relapse. So even though I’m over some serious infection hurdles, and even though the majority of death risk is clustered in the first three months post-transplant, I’m about to start facing the next challenges.

But I’m happy to be healthy, at least for now. And Greg and I are both very glad to be home. But I think we will both miss our deluxe apartment in the sky-hi-hi. And just for memento, here are some photos of the view we’ve lived with for the last 75 days:

The Prudential Building (tallest), and a couple of others that no one cares about.

Christian Science weirdos. Despite being cuh-ray-zee, their buildings are "truly beautiful to behold," including this lovely library.

More Christian "Scientists," with their absolutely lovely buildings (all the buildings in view are CS buildings in the famed "Church Park.") The shadow cast is from our sixties-built, 1984-style 12-story building (not run by the Christian Scientists . . . as far as we know).

My last post was an honest and authentic expression of my thoughts and feelings about my current state of being. I wasn’t hiding anything. But there is something else going on.

This morning I awoke with a runny nose and some congestion. This could be a minor bacterial infection, which would not likely be a problem to snuff out. But, given that my mucus is clear, bacterial infection seems unlikely. Viral infection is more consistent with that sign. It could be one of a number of common viruses that cause runny nose. For some of these, anti-viral treatments are available. For many, the viruses don’t even have names, but they don’t cause dangerous infections either. I’m hoping for one of these, of course. It could be the flu, and (despite rapidly increasing resistance) that is treatable with osteltamivir. But it could be something much more dangerous: the seemingly innocuous, simple, common cold.

While the common cold causes the mildest of infection in immunocompetent people, in me, it could be a disaster. Permanent scarring of the lungs is one outcome; death is another. As no treatment for the common cold exists (though a number of experimental therapies are soon to help out), recovery relies on one’s immune system entirely. Chicken soup may soothe, but it doesn’t cure.

Viral infections are defeated by lymphocytes. The two main groupings of lymphocytes are T-cells and B-cells. T-cells circulate in our blood, looking for proteins that are not self. When one is found, the T-cell starts dividing, and some of those T-cells seek out B-cells. The T-cells notify B-cells of the presumptive invader, and through one of the most amazing biological processes ever elucidated, germ-specific antibodies are produced. Those antibodies ultimately cause cells infected with viruses to die (among other things).

So T-cells initiate (and later suppress) immune response. B-cells primarily give rise to antibodies. The problem for me is that I don’t have very many of either of these cells. Unlike neutrophils (white blood cells that primarily fight bacterial infection) and platelets, many developmental intermediates come between stem cell and mature lymphocyte, and it can take up to nine months for mature lymphocytes to appear after transplantation. I do have a few lymphocytes from before the transplant, but it’s not clear that they will be of much use.

At this point, I just have to wait. If matters get worse, I’ll get a nose swab tomorrow. That might reveal a treatable virus or an untreatable virus. Maybe I don’t have a virus. I just don’t know right now, but in addition to being energetic and happy, I’m starting to get pretty scared.

Solitary wasps, like most animals, live their life . . . well, in solitude. Except to mate, they tend to stay away from other members of their own species. Some build small nests for their young, and some provide a modicum of parental care—the first steps toward social habit—but they do not live together in groups.

Social wasp colonies come in a variety of flavors. Some are composed of tentatively co-existing individuals, and little cooperation happens, except to share a nest. Some social wasps join together to make a group, and they fight to see who gets to be the queen. The one that wins gets to lay eggs, subjugates the others, and the others often try relentlessly to overthrow her rule; they want to lay eggs too, and they have the ovaries to do so, but they often just settle for being a worker, a forager, a builder—and if they lay an egg or two, it’s surreptitiously. I think it’s easy to see that this is a rather unstable social group, and even in these groups there are cycles of social behavior interrupted with solitary behavior. Both social and solitary interests are obvious.

Other social wasps are more interconnected. Some wasps in Central and South America (including Apoica) form large colonies of individuals who cooperate extremely well. In this derived situation, the worker wasps are much more numerous, and they now run the show—they subjugate the queens, often kicking potential or undesirable queens out of the nest. And the workers are workers, forever. They can’t lay eggs. (They just don’t have developed ovaries; there are exceptions of course, but in general, they don’t.) Only the queens have the properly developed organs needed to lay eggs. Here, we see the first permanent and most fundamental subdivision of labor necessary for stable social habit: The division of labor between the reproductives and the sterile workers.

The workers often come in different shapes and sizes; the queen differs from them. These differently equipped sterile workers work—they defend the nest; they forage for food, water and wood, which they macerate into pulp for the nest; they repair damage; they build new parts; they feed the young; and they dispose of the dead. The queen does none of these. Well, in some instances she may initiate the paper cells into which she lays the eggs, but other than that, she lays eggs and does little more.

None of these wasps are ever alone; when the colony gets too big, a group of queens and a group of workers, and rarely a small cohort of males (the workers are all female) fly to a new site and begin a new nest. The solitary life has been completely abandoned; the division of labor has made sure of that. These wasps are almost certainly locked, or approaching being locked, into sociality. The queen doesn’t forage and the workers all work. They have specialized so much that reversal to the solitary habit would be difficult . . . but it does happen.

Rogue wasps defy the structure and reverse in their behavior to the ancestral, the solitary. They eat food, take resources, enjoy protection, and contribute nothing. Sometimes they are outright aggressive (recall, solitary wasps don’t like to be around others). They lay eggs (against the rules), and their offspring may inherit their tendencies. They are commonly called “cheaters,” because they don’t keep the social compact. They often lose in their mission that if unchecked could disrupt the entire social system. They are ejected, or killed by other workers. But sometimes, their rogue efforts go unchecked, and the entire colony then can be at risk of collapse. Because they shrug off their roll as worker (no doubt due to a random mutation), and reject the division of labor upon which the colony is based, the entire system can fail.

Other wasps have taken these divisions of labor even further. In some hornets, for example, preliminary evidence suggests that the larvae of the nests, the young, are the only individuals who can digest food. The adults feed the larvae, and the larvae feed back to the adults digested vomit and spit. If the adults are separated from the larvae, they die of starvation.

This work, ongoing in my lab, is preliminary, as I said, but intriguing if true. This would mean that the genes to digest food (which they all have) have been silenced in the adults, and only the workers express those genes and have those proteins and enzymes. The larvae have become workers of a new and specialized type. They have become the digesters of the colony. They have become the stomach. Division of labor has arrived at a new, extreme level: the development of tissues, organs.

So why am I writing about all of this? Partly, of course, because this is the stuff I think about all the time: wasps, and the transition for solitary to social. But I see clear connections to our bodies, and to cancer. My view is not novel, to be sure, but for me it is comforting, in a way.

Each of us is a giant colony of intimately cooperating individual cells. They all descend from a single cell. At the first division, they could separate and go their own way, like bacteria do all the time. But they don’t, at least not usually. Sometimes this is exactly what happens. A very good friend of mine was in the early stages of pregnancy years ago, before I knew her. It isn’t clear exactly what happened, but something like this is plausible: At some point during the early stages, an unfertilized egg, or the embryo’s cells, or some cell incurred a random mutation. The mutation caused the cell to revert to its ancestral, primitive instincts. That one cell shrugged off the social contract and started dividing without control. The cells would divide and go their own way, just like their ancestral bacterial brethren, with no cooperative instinct remaining. In other words, one of the embryonic cells became a “cheater” in the social contract. It didn’t play its roll, take its position as a worker, or as they are commonly called, a differentiated cell type. The cheater had the potential to destroy the entire colony, my friend. In wasps, these mutants are called “cheaters.” When it happens in us, we call it cancer. (My friend has been cancer-free for years, thanks to chemotherapy.)

But usually, the cells all stay in line. They don’t divide and go their own way; they divide, and stay, and differentiate into tissues—various subcastes of the worker caste. Once we’re born, these cells do various things: they defend the body; they distribute food; they repair damage; they build new parts; and they dispose with the dead. The sex cells do none of these. Sound familiar?

For my cancer, the correspondence is crystal clear. In my case, the particular mutation that occurred was demonstrated genetically. In my case two of my chromosomes in a single cell physically crossed over on another. And when the crossing over occurred, the top part of one chromosome was attached to the bottom of the other, and vice versa. This is a common enough occurrence, especially for germ, or sex cells (you know, our queen caste). But in this case, when this happened, a particular gene, named bcl-2, was placed in contact with a so-called hyper-promoterenhancer‡—a region of DNA that controls the expression, the copy rate, of a gene. Bcl-2 makes a protein, and placed next to this hyper-promoterenhancer, it started making a lot of this protein.

This particular protein—from an ancient gene that we share with nearly all cellular life—in multi-cellular organisms controls a phenomenon seen in their cells called apoptosis, programmed cell death. Programmed cell death is a fundamental part of the social contract of our bodies, our apoikas of individual cells. In such a group environment, cells can’t divide without end, and they can’t stay forever. Cells must die sometimes, and make way for other cells, else the group of cells—our bodies—may have problems.

And here was the crux of my problem. The more bcl-2 that is expressed, the more easily a cell can resist signals to kill itself. So in me, when bcl-2 started being hyper-expressed in that one cell, it became immortal. And with that, the social contract was broken, and the cell started off on its own way, dividing and giving to all its daughter cells the same tendencies. As this social cheater continued to pursue its selfish interest, the whole colony—my body—started having problems. And I got sick, as those immortal daughters became so numerous that they began to clog up passageways, organs, and vessels.

This is the natural history of my cancer, follicular b-cell lymphoma, the best example that proves cancer cells are nothing more than cheater wasps at the nest. From their perspective (that is, from a selection standpoint), being freed from programmed cell death ain’t a bad thing at all. Individuals that leave more offspring win, right? This cell was on Logan’s Run . . . and having lots of babies at the same time. The problem is, all those cells that are (were?) in my body don’t have global knowledge, and so they don’t realize that they are sealing their own fate: If the colony dies, so do they, in this case. There is no complete reversal to the free-living single cell. We’ve evolved too far for that. Or have we . . . (more on that later).

This is my view. I just wanted to share it. I am comforted by it, because I understand the how and the why of my cancer. I have never once asked “Why is God doing this to me?” That’s just never been in my head. I know why I have cancer, and I understand that the cancer cells in my body—once freed from the social contract—are just like bacterial invaders. They are trying to make their way, and reproduce, like all other creatures. It’s simply an unavoidable consequence of nature.

‡UPDATE: The distinction between a promoter and an enhancer is subtle, and I won’t go into it here. But I needed to correct it, because in an attempt to write generally, what I wrote was technically incorrect.

I hear people puzzle over this question often. Oh, not so much about why I have cancer, but why cancer exists. In a world filled with bizarre, pre-enlightenment notions of “knowledge” that competes for our attention, it’s easy to see why so many would be confused. Luckily, we know exactly why cancer exists. It’s no mystery, and it certainly doesn’t require mystical explanation (though I’ve been astonished at how many attribute it to non-material forces).

Cancer happens because change is the fundamental property of living things. That change can happen in populations, or it can happen in individuals. Somewhere along the way, probably in the early 2000′s, one of my b-cells—that important component of the immune system that generates those amazing chemicals called antibodies . . . well . . . got changed. The change was random. I do not use this word—random—in the unfortunate way so many are today, to mean improbable, which is the precise opposite of its actual meaning. The change certainly was improbable in that single cell, in my body; such changes, however, are highly probably across populations where cells are changing all the time. But when I say random, I mean that it was just as likely to occur in the cell that it occurred in as it was to occur in any b-cell, and the change’s occurrence was without direction, without intention.

The details of the change in my b-cell are well known, and in my case they were demonstrated genetically in Manhattan at the time of my formal diagnosis with follicular lymphoma. Most say something went wrong; I don’t see it that way. Oh, I’m not one of those infuriating bright-siders who say absurd things like they’re glad they got cancer, or whatever other garbage they have to tell themselves so they can grapple with their mortality. I just know biology, and life is change. Populations of cells change just as populations of wasps change. One of my cells changed. That’s it. Maybe, it could’ve been an advantageous change, but it wasn’t, at least not for the whole of me (but from the reproductive perspective of the b-cell, it certainly was. . . more on that later).

The relevant behavioral change in that singe b-cell allowed it to reproduce without bound, and so it and its daughters have been busy clogging my body with their bodies—with too much of me.

Some might find this view cold. Perhaps. But it is the truth. I happen to be comforted by the knowledge of the true nature of the natural history of cancer. As a famous biologist once wrote, “there is grandeur in this view of life.”